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- EMDB-32119: Cryo-EM structure of PYD-deleted human NLRP3 hexamer -

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Basic information

Entry
Database: EMDB / ID: EMD-32119
TitleCryo-EM structure of PYD-deleted human NLRP3 hexamer
Map datacryo-EM map of PYD-deleted human NLRP3 hexamer
Sample
  • Complex: human NLRP3 (PYD-deleted) hexamer
    • Protein or peptide: NACHT, LRR and PYD domains-containing protein 3
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
  • Ligand: 1-[4-(2-oxidanylpropan-2-yl)furan-2-yl]sulfonyl-3-(1,2,3,5-tetrahydro-s-indacen-4-yl)urea
KeywordsNLR / NOD-like receptor / NLRP3 / Inflammasome / IMMUNE SYSTEM
Function / homology
Function and homology information


small molecule sensor activity / detection of biotic stimulus / cysteine-type endopeptidase activator activity / phosphatidylinositol phosphate binding / positive regulation of T-helper 2 cell differentiation / NLRP3 inflammasome complex assembly / interphase microtubule organizing center / positive regulation of T-helper 2 cell cytokine production / positive regulation of type 2 immune response / NLRP3 inflammasome complex ...small molecule sensor activity / detection of biotic stimulus / cysteine-type endopeptidase activator activity / phosphatidylinositol phosphate binding / positive regulation of T-helper 2 cell differentiation / NLRP3 inflammasome complex assembly / interphase microtubule organizing center / positive regulation of T-helper 2 cell cytokine production / positive regulation of type 2 immune response / NLRP3 inflammasome complex / peptidoglycan binding / osmosensory signaling pathway / phosphatidylinositol-4-phosphate binding / negative regulation of non-canonical NF-kappaB signal transduction / pattern recognition receptor signaling pathway / negative regulation of interleukin-1 beta production / microtubule organizing center / positive regulation of interleukin-4 production / negative regulation of NF-kappaB transcription factor activity / pyroptotic inflammatory response / positive regulation of cysteine-type endopeptidase activity involved in apoptotic process / negative regulation of acute inflammatory response / The NLRP3 inflammasome / protein maturation / Purinergic signaling in leishmaniasis infection / signaling adaptor activity / molecular condensate scaffold activity / positive regulation of interleukin-1 beta production / Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement / protein homooligomerization / Cytoprotection by HMOX1 / Metalloprotease DUBs / cellular response to virus / ADP binding / defense response / negative regulation of inflammatory response / positive regulation of inflammatory response / positive regulation of non-canonical NF-kappaB signal transduction / SARS-CoV-1 activates/modulates innate immune responses / protein-macromolecule adaptor activity / positive regulation of NF-kappaB transcription factor activity / cellular response to lipopolysaccharide / DNA-binding transcription factor binding / sequence-specific DNA binding / molecular adaptor activity / inflammatory response / Golgi membrane / innate immune response / apoptotic process / SARS-CoV-2 activates/modulates innate and adaptive immune responses / endoplasmic reticulum / signal transduction / ATP hydrolysis activity / positive regulation of transcription by RNA polymerase II / mitochondrion / extracellular region / ATP binding / identical protein binding / membrane / nucleus / cytoplasm / cytosol
Similarity search - Function
NACHT-associated domain / Fish-specific NACHT associated domain / Fish-specific NACHT associated domain / NACHT, LRR and PYD domains-containing protein, helical domain HD2 / NLRC4 helical domain HD2 / NOD2, winged helix domain / NOD2 winged helix domain / DAPIN domain / DAPIN domain profile. / PAAD/DAPIN/Pyrin domain ...NACHT-associated domain / Fish-specific NACHT associated domain / Fish-specific NACHT associated domain / NACHT, LRR and PYD domains-containing protein, helical domain HD2 / NLRC4 helical domain HD2 / NOD2, winged helix domain / NOD2 winged helix domain / DAPIN domain / DAPIN domain profile. / PAAD/DAPIN/Pyrin domain / NACHT nucleoside triphosphatase / NACHT domain / NACHT-NTPase domain profile. / PAAD/DAPIN/Pyrin domain / Leucine rich repeat, ribonuclease inhibitor type / Leucine Rich repeat / Death-like domain superfamily / Leucine-rich repeat / Leucine-rich repeat domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
NACHT, LRR and PYD domains-containing protein 3
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.23 Å
AuthorsOhto U / Shimizu T
Funding support Japan, 4 items
OrganizationGrant numberCountry
Ministry of Education, Culture, Sports, Science and Technology (Japan)19H03164 Japan
Ministry of Education, Culture, Sports, Science and Technology (Japan)20K16274 Japan
Ministry of Education, Culture, Sports, Science and Technology (Japan)20K15730 Japan
Ministry of Education, Culture, Sports, Science and Technology (Japan)19H00976 Japan
CitationJournal: Proc Natl Acad Sci U S A / Year: 2022
Title: Structural basis for the oligomerization-mediated regulation of NLRP3 inflammasome activation.
Authors: Umeharu Ohto / Yukie Kamitsukasa / Hanako Ishida / Zhikuan Zhang / Karin Murakami / Chie Hirama / Sakiko Maekawa / Toshiyuki Shimizu /
Abstract: SignificanceThe nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) is a pattern recognition receptor that forms an inflammasome. The cryo-electron ...SignificanceThe nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) is a pattern recognition receptor that forms an inflammasome. The cryo-electron microscopy structure of the dodecameric form of full-length NLRP3 bound to the clinically relevant NLRP3-specific inhibitor MCC950 has established the structural basis for the oligomerization-mediated regulation of NLRP3 inflammasome activation and the mechanism of action of the NLRP3 specific inhibitor. The inactive NLRP3 oligomer represents the NLRP3 resting state, capable of binding to membranes and is likely disrupted for its activation. Visualization of the inhibitor binding mode will enable optimization of the activity of NLRP3 inflammasome inhibitor drugs.
History
DepositionOct 30, 2021-
Header (metadata) releaseMar 9, 2022-
Map releaseMar 9, 2022-
UpdateJun 26, 2024-
Current statusJun 26, 2024Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.015
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.015
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7vtp
  • Surface level: 0.015
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7vtp
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_32119.png

Downloads & links

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Map

FileDownload / File: emd_32119.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationcryo-EM map of PYD-deleted human NLRP3 hexamer
Voxel sizeX=Y=Z: 1.245 Å
Density
Contour LevelBy AUTHOR: 0.015 / Movie #1: 0.015
Minimum - Maximum-0.026167514 - 0.074191526
Average (Standard dev.)0.00029208345 (±0.004275565)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions200200200
Spacing200200200
CellA=B=C: 249.0 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.2451.2451.245
M x/y/z200200200
origin x/y/z0.0000.0000.000
length x/y/z249.000249.000249.000
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ330330330
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS200200200
D min/max/mean-0.0260.0740.000

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Supplemental data

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Sample components

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Entire : human NLRP3 (PYD-deleted) hexamer

EntireName: human NLRP3 (PYD-deleted) hexamer
Components
  • Complex: human NLRP3 (PYD-deleted) hexamer
    • Protein or peptide: NACHT, LRR and PYD domains-containing protein 3
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
  • Ligand: 1-[4-(2-oxidanylpropan-2-yl)furan-2-yl]sulfonyl-3-(1,2,3,5-tetrahydro-s-indacen-4-yl)urea

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Supramolecule #1: human NLRP3 (PYD-deleted) hexamer

SupramoleculeName: human NLRP3 (PYD-deleted) hexamer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: NACHT, LRR and PYD domains-containing protein 3

MacromoleculeName: NACHT, LRR and PYD domains-containing protein 3 / type: protein_or_peptide / ID: 1 / Number of copies: 6 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 106.298539 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: HHHHHHDYKD DDDKLEVLFQ GPEFCKMKKD YRKKYRKYVR SRFQCIEDRN ARLGESVSLN KRYTRLRLIK EHRSQQEREQ ELLAIGKTK TCESPVSPIK MELLFDPDDE HSEPVHTVVF QGAAGIGKTI LARKMMLDWA SGTLYQDRFD YLFYIHCREV S LVTQRSLG ...String:
HHHHHHDYKD DDDKLEVLFQ GPEFCKMKKD YRKKYRKYVR SRFQCIEDRN ARLGESVSLN KRYTRLRLIK EHRSQQEREQ ELLAIGKTK TCESPVSPIK MELLFDPDDE HSEPVHTVVF QGAAGIGKTI LARKMMLDWA SGTLYQDRFD YLFYIHCREV S LVTQRSLG DLIMSCCPDP NPPIHKIVRK PSRILFLMDG FDELQGAFDE HIGPLCTDWQ KAERGDILLS SLIRKKLLPE AS LLITTRP VALEKLQHLL DHPRHVEILG FSEAKRKEYF FKYFSDEAQA RAAFSLIQEN EVLFTMCFIP LVCWIVCTGL KQQ MESGKS LAQTSKTTTA VYVFFLSSLL QPRGGSQEHG LCAHLWGLCS LAADGIWNQK ILFEESDLRN HGLQKADVSA FLRM NLFQK EVDCEKFYSF IHMTFQEFFA AMYYLLEEEK EGRTNVPGSR LKLPSRDVTV LLENYGKFEK GYLIFVVRFL FGLVN QERT SYLEKKLSCK ISQQIRLELL KWIEVKAKAK KLQIQPSQLE LFYCLYEMQE EDFVQRAMDY FPKIEINLST RMDHMV SSF CIENCHRVES LSLGFLHNMP KEEEEEEKEG RHLDMVQCVL PSSSHAACSH GLVNSHLTSS FCRGLFSVLS TSQSLTE LD LSDNSLGDPG MRVLCETLQH PGCNIRRLWL GRCGLSHECC FDISLVLSSN QKLVELDLSD NALGDFGIRL LCVGLKHL L CNLKKLWLVS CCLTSACCQD LASVLSTSHS LTRLYVGENA LGDSGVAILC EKAKNPQCNL QKLGLVNSGL TSVCCSALS SVLSTNQNLT HLYLRGNTLG DKGIKLLCEG LLHPDCKLQV LELDNCNLTS HCCWDLSTLL TSSQSLRKLS LGNNDLGDLG VMMFCEVLK QQSCLLQNLG LSEMYFNYET KSALETLQEE KPELTVVFEP SW

UniProtKB: NACHT, LRR and PYD domains-containing protein 3

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Macromolecule #2: ADENOSINE-5'-DIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-DIPHOSPHATE / type: ligand / ID: 2 / Number of copies: 6 / Formula: ADP
Molecular weightTheoretical: 427.201 Da
Chemical component information

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM

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Macromolecule #3: 1-[4-(2-oxidanylpropan-2-yl)furan-2-yl]sulfonyl-3-(1,2,3,5-tetrah...

MacromoleculeName: 1-[4-(2-oxidanylpropan-2-yl)furan-2-yl]sulfonyl-3-(1,2,3,5-tetrahydro-s-indacen-4-yl)urea
type: ligand / ID: 3 / Number of copies: 6 / Formula: 7YN
Molecular weightTheoretical: 402.464 Da
Chemical component information

ChemComp-7YN:
1-[4-(2-oxidanylpropan-2-yl)furan-2-yl]sulfonyl-3-(1,2,3,5-tetrahydro-s-indacen-4-yl)urea

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
Details: 25 mM HEPES-NaOH (pH 7.5), 0.2 M NaCl, 1 mM MgCl2, 0.5 mM TCEP, 1.0 mM ADP, 0.05 mM MCC950
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 68.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: D3 (2x3 fold dihedral) / Resolution.type: BY AUTHOR / Resolution: 3.23 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 105139
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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